Although the natural history of HIV-1 infection has been rather well defined in regard to progressive loss of immunologic integrity, consequent opportunistic disease, and additional neurologic and hematologic sequelae, the molecular and biologic basic of viral pathogenesis is poorly understood. Precedents from other lentiviral diseases indicate that replication patterns of lentiviruses in vitro and in vivo differ substantially and that a complex interplay between viral and host specific factors influences dramatically the replication of virus and expression of disease. In this project, we propose to: (i) define the replicative level and pattern of HIV-1 during natural infection of adult and pediatric populations and the relationship between viral replication in vivo and disease stage, disease progression, and immunologic deterioration; (ii) determine the prevalence and biological significance of naturally-occurring HIV-1 populations that exhibit altered virulence; (iii) identify and characterize in a genetically-defined experimental system determinants of virulence and cell tropism in naturally-occurring HIV-1 viruses; and (iv) characterize in the genetically-defined and autologous experimental system (molecularly cloned virus and serum from the same subject), the development of type and group specific neutralizing antibodies, and the relationship between viral antigenic variation, host immunologic surveillance, and viral replication levels during natural HIV-1 infection. The results of the proposed studies should provide new insight into mechanisms of viral pathogenesis and quantitative data regarding HIV-1 replication patterns in vivo.